No abstract

Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood–brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug‐targeting approaches and targeted nanotechnology‐based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.

This paper describes the first covalent synthesis of kappa-carrageenan-3'-azido-3'-deoxythymidine (AZT) conjugates. A succinate diester spacer was used to covalently couple AZT onto kappa-carrageenan, resulting in a tripartite prodrug. Two methods (UV and radioactive counting) are described and validated to determine the AZT loading onto the kappa-carrageenan carrier. This polymeric carrier, through its own intrinsic anti-HIV activity, is expected to act not only as a drug delivery agent but also as an anti-HIV agent. Synergism between the two drugs (kappa-carrageenan and AZT) was demonstrated when MT-4 cells were preincubated with the kappa-carrageenan-AZT conjugate prior to HIV-1-infection. A threshold of AZT loaded onto the kappa-carrageenan was required to achieve this synergistic effect. Such kappa-carrageenan-AZT conjugates could be of great therapeutic interest because these conjugates, which contain a low AZT concentration, present improved anti-HIV activities relative to free AZT. Moreover, kappa-carrageenan is a well-tolerated biopolymer, already used in the food industry.